Protein kinase C-alpha: a novel target for the therapy of androgen-independent prostate cancer? (Review-hypothesis).
Prostate cancer is a leading cause of cancer death among men in Western countries. A major reason for this is that the malignancy often progresses to an androgen-independent phenotype that is highly aggressive and unresponsive to available therapies. Protein kinase C (PKC) is an isozyme family with at least eleven mammalian members that play important roles in cell growth regulation and differentiation. Based on the emerging understanding of the role played by PKC isozymes in the regulation of prostate cancer cell growth and programmed death, in this report we develop the hypothesis that a defective PKC-a-mediated apoptotic pathway in androgen-independent human prostate cancer cells has allowed the cells to acquire a selective growth advantage by overexpression of PKC-a and that this adaptive response renders the cells dependent on constitutively active PKC-a for their survival. Studies reviewed in this report provide strong evidence that expression of constitutive PKC-a activity is required for the survival and growth of androgen-independent human prostate cancer cells, but direct evidence for this is still lacking. We outline experimental approaches that will be required to definitively test the importance of PKC-a to androgen-independent human prostate cancer cell growth and survival. If constitutive PKC-a activity is in fact found to be required for the growth and survival of androgen-independent human prostate cancer, then the development of PKC-a-targeted therapeutics for use in the clinical treatment of prostate cancer will be justified.
O'Brian
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Department of Cell Biology, M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 173, Houston, TX 77030, USA.
D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D010703:Phorbol Esters / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051571:Protein Kinase C-alpha; D014407:Tumor Cells, Cultured
D000728:Androgens; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D010703:Phorbol Esters; C496628:PRKCA protein, human; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha